UNASSIGNED: Lower-risk myelodysplastic neoplasms (LR-MDS) comprise the majority of MDS. Despite favourable prognoses, some patients remain at risk of rapid progression. We aimed to define the mutational profile of LR-MDS using next-generation sequencing (NGS), Sanger Sequencing (SSeq), and pyrosequencing.
UNASSIGNED: Samples from 5 primary LR-MDS (67 exons of SF3B1, U2AF1, SRSF2, ZRSR2, TET2, ASXL1, DNMT3A, TP53, and RUNX1 genes) were subjected to NGS. Next, a genomic study was performed to test for the presence of identified DNA sequence variants on a larger group of LR-MDS patients (25 bone marrow [BM], 3 saliva [SAL], and one peripheral blood [PB] sample/s). Both SSeq (all selected DNA sequence variants) and pyrosequencing (9 selected DNA sequence variants) were performed.
UNASSIGNED: Next-generation sequencing results identified 13 DNA sequence variants in 7 genes, comprising 8 mutations in 6 genes (ASXL1, DNMT3A, RUNX1, SF3B1, TET2, ZRSR2) in LR-MDS. The presence of 8 DNA variants was detected in the expanded LR-MDS group using SSeq and pyrosequencing. Mutation acquisition was observed during LR-MDS progression. Four LR-MDS and one acute myeloid leukaemia myelodysplasia-related patient exhibited the presence of at least one mutation. ASXL1 and SF3B1 alterations were most commonly observed (2 patients). Five DNA sequence variants detected in BM (patients: 9, 13) were also present in SAL.
UNASSIGNED: We suggest using NGS to determine the LR-MDS mutational profile at diagnosis and suspicion of disease progression. Moreover, PB and SAL molecular testing represent useful tools for monitoring LR-MDS at higher risk of progression. However, the results need to be confirmed in a larger group.

Background: Acute myeloid leukemia post cytotoxic therapy (AML-pCT) among breast cancer (BC) survivors represents a life-threatening complication. This study aims to assess the clinical outcomes of AML-pCT post BC. Methods: An analysis of all AML patients treated at a single hematology center (2000-2023) was performed to select patients with AML-pCT post BC. We applied the 2022 ELN criteria to define the genetic risk. Results: Among 847 AML patients, 28 were diagnosed with AML-pCT following BC. Complex karyotype (CK) occurred in 23.8% of patients. The median overall survival (OS) was 40 months. The survival outcomes were better after allogenic hematopoietic stem cell transplantation (alloHCT) treatment compared to chemotherapy alone (median OS: 47 versus 7 months, p = 0.008). Patients demonstrating CK showed lower survival compared to those without CK (2-year OS: 25.0% versus 66.2%, p = 0.0048). The multivariable Cox proportional hazards regression model indicated that treatment with alloHCT emerged as a significant factor associated with improved OS. The treatment was associated with superior OS (HR = 0.07, 95% CI = 0.01-0.86, p = 0.04). Conclusions: Patients with AML-pCT following BC were characterized with the highest frequency of adverse genetic risk profiles and demonstrated worse survival rates. AlloHCT should be performed as early as possible in such patients. The growing need for studies on inherited cancer susceptibility underscores the importance of close AML-pCT development monitoring in BC survivors.

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We report three adult patients with primary immunodeficiency (PID) treated with reduced-intensity allogenic hematopoietic cell transplantation (HCT) with fludarabine/treosulfan conditioning and graft-versus-host disease (GvHD) prophylaxis with alemtuzumab and a calcineurin inhibitor.
Patient 1, a 51-year-old male, had common variable immunodeficiency (CVID) with protein-losing enteropathy. Patient 2 was a 29-year-old woman with STAT3 (signal transducer and activator of transcription 3)-dependent hyper-IgE syndrome (HIES). Patient 3 was a 25-year-old male with XIAP (X-linked inhibitor of apoptosis)-deficiency presenting as treatment-refractory granulomatous enteropathy. Engraftment occurred in all three patients, with 100% donor chimerism in blood. Two patients survived, whereas the patient with CVID died due to infection.
This series highlights issues of transplantation for PID in adults and treosulfan-based conditioning, which is feasible for PID patients; infectious complications are the major issue of concern.

The purpose of this retrospective study was to study the correlation between donor age (DA) and non-relapse mortality (NRM) and relapse incidence (RI) among patients treated with allogeneic hematopoietic cell transplantation (aHCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a single Canadian center. Data from 125 consecutive patients transplanted with a matched related or unrelated donor between 2015 and 2020 were analyzed using multivariable models. After a median follow-up of 2.8 years, the cumulative incidences of NRM and relapse were 19% and 35% at 5 years. Despite being independently associated with NRM and relapse-free survival (RFS), DA was not associated with RI. The independent determinants of NRM in addition to DA were patient age and hematopoietic cell transplantation comorbidity index (HCT-CI), independently of donor kinship. The effect of DA on NRM was found to be significantly increased over the age of 50 years. DA was not associated with incidence of acute graft-versus-host disease (aGVHD) but showed an association with the occurrence of chronic GVHD (cGVHD). In conclusion, younger donors should be favored to limit NRM and increase RFS in HLA-matched aHCT. The etiological mechanisms behind the association of DA with higher NRM remain to be elucidated.

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by the presence of cytopenias, ineffective hematopoiesis and frequent transformation into secondary acute myeloid leukemia (secAML). Recent genomic studies provide unprecedented insight into the molecular landscape of clonal proliferation in MDS. Genetic diversity of both MDS and secAML subclones cannot be defined by a single somatic mutation. Mutations of the founding clone may survive over implemented chemotherapy and allogenic hematopoietic cell transplantation (alloHCT), but new subclonal mutations may also appear. Next generation sequencing (NGS) makes it possible to define the mutational profile of disease subclones during the treatment course and has a potential in pre- and post-alloHCT monitoring. Understanding the molecular pathophysiology of MDS may soon allow for monitoring the course of disease and personalized treatment depending on the mutational landscape. In the present paper we report, for the first time in MDS, ASXL1 c.1945G>T, TET2 c.4044+2dupT and c.4076G>T sequence variants. Moreover, we detected RUNX1 c.509-2A>C and SF3B1 c.1874G>T sequence variants. Furthermore, we verify the clinical utility of NGS and pyrosequencing in MDS and secAML.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach for patients with certain hematological diseases, including several forms of lymphoma and leukemia. Besides several treatment-associated risks, transplanted patients are at an increased risk of developing osteoporosis. The underlying pathophysiology is complex and includes factors influenced directly by the disease as well as applied therapies like irradiation, chemotherapy and adjuvant immunosuppressive agents. In addition, patients are prone to secondary hypogonadism, and many patients will require long-term glucocorticoid therapy to mitigate graft-versus-host reactions. All these factors contribute to bone loss, but the individual risk profile may vary greatly. This review summarizes our knowledge on bone loss following allogenic HCT and provides screening and treatment recommendations.

Objectives: Authors assessed the impact of ruxolitinib (RUX) on steroid-refractory graft-versus-host disease (SR-GVHD) patients.Methods: Studies published before January 2019 were identified by electronic search of MEDLINE, EMBASE, Cochrane Library, Clinical Trials.Gov and Web of Science databases.Results: Sixteen cohort studies (414 adults) were included whose methodological quality ranged from poor to good. Pooled outcomes such as the response rates, steroid dose reduction, 1-year overall survival, overall infection, and grade 3 to 4 cytopenia were calculated separately for adults with steroid-refractory acute GVHD (aGVHD) and chronic GVHD (cGVHD). Further, the overall response rates were analyzed according to the affected organ. Adults with aGVHD as well as cGVHD showed high response with RUX, and steroid dose reduction was observed in both cases. Infection rates and cytopenia were important safety concerns for both aGVHD and cGVHD.Conclusion: Notwithstanding the need of randomized controlled trials to confirm the effect of RUX on SR-GVHD, response rates among adults with aGVHD and cGVHD seem to be high with the use of RUX as a salvage treatment, particularly in cases with gastrointestinal and cutaneous involvement. However, high rates of myelosuppression and infection remain a cause for concern regardless of aGVHD or cGVHD.

Association between low counts of herpesvirus-specific T cells and subsequent relapse of hematologic malignancy has been shown in two retrospective studies.
Here we present results of a prospective validation study. Multiple subsets of Epstein-Barr virus (EBV)-specific T cells were measured in 69 patients on day 56 and 84, using intracellular flow cytometry after incubation of blood mononuclear cells (MNCs) with EBV peptides or lysate.
All EBV T-cell subsets measured, both on day 56 and 84, were lower in patients who did versus did not subsequently relapse. This was most significant for day 56 EBV lysate-stimulated CD8 T cells producing interferon-gamma. Patients with day 56 counts of this subset >5/µL had a significantly lower likelihood of relapse compared with those with ≤5/µL (subhazard ratio, 5.7; P = 0.007). Similar significant associations were shown for a total of seven EBV T-cell subsets on day 56 and nine subsets on day 84. However, sensitivity and specificity of relapse prediction using the count of any subset was low (area under the curve of receiver-operator characteristic curve was <0.8).
In conclusion, the association between EBV T-cell counts and subsequent relapse is valid. However, its clinical utility appears to be limited.